Sinus delivery of sustained release therapeutics

ABSTRACT

The invention provides biodegradable implants for treating sinusitis. The biodegradable implants have a size, shape, density, viscosity, and/or mucoadhesiveness that prevents them from being substantially cleared by the mucociliary lining of the sinuses during the intended treatment period. The biodegradable implants include a sustained release therapeutic, e.g., an antibiotic, a steroidal anti-inflammatory agent, or both. The biodegradable implants may take various forms, such as rods, pellets, beads, strips, or microparticles, and may be delivered into a sinus in various pharmaceutically acceptable carriers.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/479,794, filed on Jun. 6, 2009, which is a divisional of U.S.application Ser. No. 10/800,162, filed on Mar. 12, 2004, now U.S. Pat.No. 7,544,192, which claims benefit of U.S. Provisional Application Ser.No. 60/454,918, filed on Mar. 14, 2003. Each of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to biodegradable implants and methods for placingone or more of these implants into a paranasal sinus. The implantsprovide local sustained release of a therapeutic agent for theprophylaxis or treatment of sinusitis. Included in the description areimplants delivered in such various forms as pellets, rods, strips, andmicroparticles.

BACKGROUND OF THE INVENTION

The paranasal sinuses are air-filled cavities within the facialskeleton. Each paranasal sinus is contiguous with a nasal cavity anddrains into the nose through a sinus ostium. Although other factors maybe involved, the development of sinusitis (inflammation of the mucosallining of the sinuses) is most often attributed to blockage of one ormore of these sinus ostia, followed by mucostasis and microbialovergrowth in the sinus cavity. Ostial blockage may stem frompredisposing anatomical factors, or inflammation and edema of the mucouslining in the area of the ostia, arising from such etiologies as viralor bacterial upper respiratory infection or chronic allergic processes.

Traditionally, sinusitis has been medically managed by the oraladministration of antibiotics and steroids. However, penetration ofthese systemically delivered agents into the sinus mucosa is limited dueto poor blood flow to the sinuses. Therapeutic agents contained inaqueous solutions, creams, or gels, for topical application in the nosehave also been formulated, but usually never travel far enough into thenose to reach the sinuses, are blocked from entering the sinuses due toobstructed ostia, or have such short contact with the sinus mucosa thatabsorption of the agent is low. For similar reasons, nasally inhaledsteroid and anti-infective aerosols that have been developed to treatsinusitis are equally ineffective.

The delivery of ampicillin from a poly(lactic-co-glycolic)acid (PLGA)film to increase residence time of the antibiotic in rabbit sinuses hasbeen investigated for the treatment of sinusitis (Min et al. MucociliaryActivity and Histopathology of Sinus Mucosa in Experimental MaxillarySinusitis: A Comparison of Systemic Administration of Antibiotic andAntibiotic Delivery by Polylactic Acid Polymer. Laryngoscope 105:835-342(1995) and Min et al. Application of Polylactic Acid Polymer in theTreatment of Acute Maxillary Sinusitis in Rabbits. Acta Otolaryngol115:548-552 (1995)). Although clinical signs of sinusitis improved, theprocedure for placing the film required that a hole be drilled throughthe anterior wall of the maxillary sinus.

Consequently, a biodegradable implant for administering a sustainedrelease therapeutic agent to the paranasal sinuses for a prolonged timeperiod without being substantially cleared by the mucociliary lining ofthe sinuses, and methods for delivering the implant in a minimallyinvasive fashion may provide significant medical benefit for patientsafflicted with sinusitis.

SUMMARY OF THE INVENTION

The present invention is a biodegradable implant for treating sinusitisthat includes a sustained release therapeutic agent dispersed within abiodegradable matrix, and which has at least one characteristic thatsubstantially prevents clearance of the implant from the sinus by itsmucociliary layer during the intended treatment period after delivery ofthe implant into the sinus. Characteristics such as size, shape,density, viscosity, mucoadhesiveness, or a combination thereof may bealtered to substantially prevent this clearance.

The biodegradable implant may include various therapeutic agents,including, but not limited to, anti-infective agents, anti-inflammatoryagents, and combinations thereof. Examples of anti-infective agentsinclude antibacterial agents, antifungal agents, antiviral agents, andantiseptics. The anti-inflammatory agent may be a nonsteroidalanti-inflammatory agent or a steroidal anti-inflammatory agent. In apreferred variation, steroidal anti-inflammatory agents are used.

The matrix of the implant may be made from any biodegradable andbiocompatible polymer, including such polymers as mucoadhesive polymers,poly(ortho esters), and poly(lactic-co-glycolic)acid (PLGA) copolymer.The biodegradable polymer matrix may also be formed as a rod, pellet,bead, strip, or microparticle, and placed in a pharmaceuticallyacceptable carrier if desired. When the biodegradable implant is amicroparticle, usually a plurality of microparticles are delivered intothe sinus to treat sinusitis. The microparticles may or may not beporous, and may have an average diameter of between about 0.1-500 μm,between about 0.1-100 μm, between about 0.1-50 μm, or between about0.1-10 μm. In some instances, the form of the biodegradable implant maychange after delivery into the sinus. For example, a poly(ortho ester)implant in the form of a strip having a series of predetermined fracturelines or zones may fracture into a plurality of smaller segments as itdegrades along the fracture lines in the sinus.

The biodegradable implant may deliver a sustained release therapeuticagent over at least about one week, over at least about two weeks, overat least about three weeks, over at least about four weeks, over atleast about six weeks, over at least about two months, or over at leastabout three months. In a preferred variation, the sustained releasetherapeutic agent is delivered into the sinus over about three weeks.

The biodegradable implants may be delivered into a sinus using devicesof various designs, but at least which include a pusher and a conduit,e.g., a catheter, needle, or angiocatheter. For example, the pusherand/or conduit may be made such that they are variably stiff along theirlengths. In addition, the opening in the conduit through which theimplant is delivered may be positioned in the conduit side wall or atthe tip. Furthermore, the distal portion of the conduit may be angulatedto facilitate access of the sinus ostium if indicated. In one variation,the distal portion is malleable such that the physician may angulate theconduit themselves just prior to accessing the sinus ostium.

The biodegradable implants and devices for their deployment may be usedin a system for treating sinusitis. In general, the system works byfirst placing the conduit having one or more implants within its lumeneither through a sinus ostium or a sinus wall. A pusher within the lumenof the conduit is then distally advanced to slidably engage theimplant(s) and move it through an opening in the distal portion of theconduit into the sinus. The opening may be in the conduit side wall ortip. Usually, the conduit will be preloaded with one or more implants.In some instances, a tool for visualizing the sinus ostium or sinus wallis desired. Examples of such tools include endoscopes and computedtomography (CT) scanners.

The biodegradable implants may also be used for reducing inflammationfrom a sinus procedure. These implants would also include a sustainedrelease therapeutic agent dispersed within a biodegradable matrix andhave at least one characteristic that substantially prevents clearanceof the implants from a sinus during a treatment period after delivery ofthe implant into the sinus. The treatment period may be of any durationwhich the physician deems is suitable to reduce the inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B are cross-sectional views of the distal portion of animplant delivery device. In FIG. 1A, the biodegradable implant isdelivered through a side opening in the conduit. In FIG. 1B, thebiodegradable implant is delivered through the tip of the conduit.

FIG. 2A is a cross-sectional view of a distal portion of a multipleimplant delivery device.

FIG. 2B is a cross-sectional view of a handle that may be coupled to thedistal portion of the multiple implant delivery device shown in FIG. 2A.

DETAILED DESCRIPTION OF THE INVENTION

The biodegradable implants of this invention may take various forms, butare generally designed to have a size and shape appropriate for theintended method of delivery, e.g., through the sinus ostium or bypuncture through a sinus wall, and a density, viscosity, and/ormucoadhesiveness such that the implant is not substantially cleared fromthe sinus over the duration of treatment. Once within the sinus, theimplant releases a therapeutic agent over a prolonged time period, forexample, over at least one week, over at least two weeks, over at leastthree weeks, or over at least four weeks or more, to treat sinusitis.

Definitions

For purposes of this description, we use the following terms as definedin this section, unless the context of the word indicates a differentmeaning.

By “sinus” it is meant all sinuses, i.e., the maxillary, ethmoid,frontal, and sphenoidal sinuses.

By “subject” it is meant mammalian subjects, preferably humans. Mammalsinclude, but are not limited to, primates, farm animals, sport animals,cats, dogs, rabbits, mice, and rats.

As used herein, the term “treat”, “treating”, or “treatment” refers tothe resolution, reduction, or prevention of sinusitis or the sequelae ofsinusitis.

As used herein, the term “therapeutic agent”, “active agent”, and “drug”are used interchangeably and refer to any substance used to treatsinusitis.

By “therapeutic amount” it is meant a concentration of therapeutic agentthat has been locally delivered to a sinus that is appropriate to safelytreat sinusitis.

Biodegradable Implants

The implants of this invention generally include a therapeutic agentdispersed within a biodegradable polymer. The therapeutic agent may behomogeneously or inhomogeneously dispersed throughout the implant.Implant compositions may vary, depending, for example, on the particulartherapeutic agent employed, duration of desired drug release, type ofsinusitis being treated, and medical history of the patient. However, inall instances, the biodegradable implant is formulated for sustainedrelease of the therapeutic agent.

Therapeutic Agents

The therapeutic agents that may be used in the biodegradable implantsinclude, but are not limited to, anti-infective agents,anti-inflammatory agents, or a combination thereof. Anti-infectiveagents generally include antibacterial agents, antifungal agents,antiviral agents, and antiseptics. Anti-inflammatory agents generallyinclude steroidal and nonsteroidal anti-inflammatory agents.

Examples of antibacterial agents that may be incorporated in thebiodegradable implants include aminoglycosides, amphenicols, ansamycins,β-lactams, lincosamides, macrolides, nitrofurans, quinolones,sulfonamides, sulfones, tetracyclines, and any of their derivatives. Inone variation, β-lactams are the preferred antibacterial agents.

β-lactams that may be included in the implants include carbacephems,carbapenems, cephalosporins, cephamycins, monobactams, oxacephems,penicillins, and any of their derivatives. In one variation, penicillins(and their corresponding salts) are the preferred β-lactams.

The penicillins that may be used in the biodegradable implants includeamdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin,aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinicacid, benzylpenicillin sodium, carbenicillin, carindacillin,clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin,methicillin sodium, mezlocillin, nafcillin sodium, oxacillin,penamecillin, penethamate hydriodide, penicillin G benethamine,penicillin G benzathine, penicillin G benzhydrylamine, penicillin Gcalcium, penicillin G hydrabamine, penicillin G potassium, penicillin Gprocaine, penicillin N, penicillin O, penicillin V, penicillin Vbenzathine, penicillin V hydrabamine, penimepicycline, phenethicillinpotassium, piperacillin, pivampicillin, propicillin, quinacillin,sulbenicillin, sultamicillin, talampicillin, temocillin, andticarcillin. In one variation, amoxicillin may be included in thebiodegradable implant. In another variation, the biodegradable implantincludes ampicllin. Penicillins combined with clavulanic acid such asAugmentin® (amoxicillin and clavulanic acid) may also be used.

Examples of antifungal agents that may be used in the biodegradableimplants include allylamines, imidazoles, polyenes, thiocarbamates,triazoles, and any of their derivatives. In one variation, imidazolesare the preferred antifungal agents.

Typically, if inclusion of an anti-inflammatory agent is desired, asteroidal anti-inflammatory agent, e.g., a corticosteroid, is employed.Examples of steroidal anti-inflammatory agents that may be used in theimplants include 21-acetoxypregnenolone, alclometasone, algestone,amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,clobetasol, clobetasone, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, and any of their derivatives. In one variation, budesonideis included in the implant as the steroidal anti-inflammatory agent. Inanother variation, the steroidal anti-inflammatory agent may bemometasone furoate. In yet another variation, the steroidalanti-inflammatory agent may be beclomethasone.

The therapeutic agent may constitute from about 5% to about 90%, about15% to about 75%, or about 30% to about 60% by weight of the implant.The amount of therapeutic agent used will usually depend on factors suchas the particular agent incorporated, the suspected etiology of thesinusitis, and the severity of clinical symptoms, but in all instanceswill usually be an amount that is therapeutic upon delivery into asinus. Ancillary agents such as topical decongestants may also beincluded.

Polymer Matrix

Selection of the biodegradable polymer matrix to be employed will varydepending on the residence time and release kinetics desired, method ofimplant delivery, particular therapeutic agent used, and the like. Anexemplary list of biodegradable polymers that may be used are describedin Heller, Biodegradable Polymers in Controlled Drug Delivery, In: “CRCCritical Reviews in Therapeutic Drug Carrier Systems”, Vol. 1. CRCPress, Boca Raton, Fla. (1987). In all instances, the polymer matrixwhen degraded results in physiologically acceptable degradationproducts. The biodegradable polymer matrix may constitute at least about10%, at least about 20%, at least about 30%, at least about 40%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, or at least about 95% by weight of the implant.

In one variation, adhesiveness of the polymer matrix to the sinus mucosais particularly desired. Mucoadhesive polymers are typicallyhydrophilic, and upon moistening, swell and become adhesive. Examples ofmucoadhesive polymers that may be employed in the biodegradable implantsinclude homopolymers of acrylic acid monomers such as polyacrylic acidand any of its pharmaceutically acceptable salts; copolymers of acrylicacid and methacrylic acid, styrene, or vinyl ethers; vinyl polymers suchas polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinylalcohol, and polyvinyl pyrrolidone; cellulosic derivatives such asmethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose;polysaccharides such as alginic acid, sodium alginate, and tragacanthgum; collagen; gelatin; and any combination thereof.

In another variation, the biodegradable matrix is made from anorthoester, alone or in combination with other monomers. In a preferredvariation, a poly(ortho ester) is used to constitute the polymer matrix.

In yet a further variation, polymers of hydroxyaliphatic carboxylicacids, either homo- or copolymers, are used to form the matrix. Forexample, polyesters including homo- or copolymers of D-lactic acid,L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, andcombinations thereof may be used. Copolymers of glycolic and lactic acidare of particular interest, where the rate of biodegradation iscontrolled by the ratio of glycolic to lactic acid. The percent of eachmonomer in poly(lactic-co-glycolic)acid (PLGA) copolymer may be 0-100%,about 20-80%, about 30-70%, or about 40-60%. In a preferred variation, a50/50 PLGA copolymer is used.

In one variation, PLGA may be combined with budesonide to form thebiodegradable sinus implant. In another variation, PLGA may be combinedwith mometasone furoate. If inclusion of an antibacterial agent isdesired in the PLGA matrix, alone or in combination with a steroidalanti-inflammatory agent, Augmentin® may be used. If first-lineantimicrobial therapy fails, or for penicillin allergy, a cephalosporinsuch as ciprofloxacin or macrolide such as erythromycin may be used inthe PLGA matrix.

The biodegradable implants may be solid or semisolid and take a varietyof suitable forms, such as rods or approximately spherical orrectangular pellets, beads, strips, or microparticles, so long as theirsize and shape is compatible with the selected sinus of implantation,and so long as the implants exhibit the desired release kinetics anddeliver an amount of drug therapeutic for the intended type ofsinusitis. In one variation, the implant is a rod having a length ofabout 1 mm to about 10 mm and a diameter of about 0.05 mm to about 5 mm.In another variation, the implant is a rod having a length of about 4 mmand a diameter of about 2 mm. In yet a further variation, the implant isa microparticle. When treating sinusitis, a plurality of thesemicroparticles with or without a carrier are delivered into the sinus.The microparticles may or may not be porous, and may have an averagediameter of between about 0.1-500 μm, between about 0.1-100 μm, betweenabout 0.1-50 μm, between about 0.1-10 μm, between about 0.1-1 μm, orbetween about 0.1-0.5 μm.

Also important is that the implant remain in the sinus during theintended period of drug delivery. The sinuses are lined with a ciliatedepithelium and a layer of mucus. The cilia beat continuously, causingthe mucous layer to slowly flow out of the sinus toward the pharynx.Accordingly, in order to effectively treat sinusitis with an implant,the implant must typically remain in the sinus long enough to deliver adrug in a therapeutic amount. The biodegradable implants of thisinvention have a mucoadhesiveness, size, shape, viscosity, and/ordensity that allows a substantial amount of the implant to remain in thesinus during the intended period of drug delivery.

Furthermore, the implant may be of a design that allows it to take aform that is different after it is delivered into the sinus from thatbefore delivery. For instance, an implant delivered into the sinus as arod or strip having a series of predetermined fracture lines or zonesmay fracture into a plurality of smaller segments as it degrades alongthe fracture lines.

Additional Agents

The implants of this invention may further include components such aspreservatives, buffers, binders, disintegrants, lubricants, and anyother excipients necessary to maintain the structure and/or function ofthe implants. Furthermore, the implants may be placed in apharmaceutically acceptable carrier, e.g., when the implants aremicroparticles, to form a suspension such as a semi-solid gel. Commongel bases include, but are not limited to, carbomer, liquid paraffin,water, glycerol, propylene glycol, hyaluronic acid or sodiumhyaluronate, or a combination thereof. The types of gels that may beformed include, e.g., inorganic and organic gels, hydrogels, ororganogels.

In addition to microparticle density, the viscosity of the gel may beadjusted to a level that allows delivery into the sinus and preventssubstantial clearance of the microparticles (implants) from the sinus.The gel may also be prepared in adhesive form (using adhesive polymerssuch as polyacrylic acid, sodium carboxymethyl cellulose, orpolyvinylpyrrolidone) to increase the contact time of the therapeuticagent with the sinus mucosa.

Release Kinetics

In general, the implants of this invention are formulated with particlesof a therapeutic agent dispersed within a biodegradable polymer matrix,and formulated to provide sustained-release of the therapeutic agent. Ifmade from a non-swellable polymer, e.g., PLGA or poly(ortho ester),release of the active agent from the matrix is probably achieved byerosion of the biodegradable polymer matrix and by diffusion of theparticulate therapeutic agent into the mucous layer of the sinus.Factors that may influence the release kinetics include suchcharacteristics as the size of the drug particles, the solubility of thedrug, the ratio of drug to polymer(s), the method of implantmanufacture, the implant surface area exposed, and the erosion rate ofthe matrix polymer(s). In the case of polymer swelling, as seen withhydrogels, a therapeutic agent is released as liquid diffuses throughexposed pathways in the implant.

The therapeutic agent may be released from the implant over a prolongedtime period including, but not limited to, at least about one week, atleast about two weeks, at least about three weeks, at least about fourweeks, at least about 6 weeks, at least about two months, or at leastabout three months. In one variation, the therapeutic agent is releasedover about two weeks to about four weeks.

Delivery Device

The biodegradable implants may be placed into the sinus using variousimplant delivery devices. The device generally includes a conduit, e.g.,a catheter, having an elongate pusher within its lumen. The conduit andpusher may be flexible or rigid, or may be designed to have varyingdegrees of stiffness along its length, e.g., the distal portion of theconduit may be stiffer than the proximal portion. In addition, thedistal portion of the conduit may be variously angulated to facilitatepositioning and advancement of the conduit through the sinus ostium. Forexample, the distal portion may be angulated from about 0° to about175°, from about 0° to about 135°, or from about 0° to about 90°.

The conduit may be made from any biocompatible material including, butnot limited to, stainless steel and any of its alloys; titanium alloys,e.g., nickel-titanium alloys; polymers, e.g., polyethylene andcopolymers thereof, polyethylene terephthalate or copolymers thereof,nylon, silicone, polyurethanes, fluoropolymers, poly (vinylchloride),and combinations thereof, depending on the amount of flexibility orstiffness desired. The pusher may be made from similar materials.

Usually, the device will be preloaded with a single implant within thelumen of the conduit, but more than one implant may be preloaded ifdesired. Once access through a sinus ostium has been obtained with theconduit, the pusher slidably engages the implant and is advanced untilthe implant exits the catheter into the sinus. An endoscope may also beused while positioning the conduit to aid with visualization of theostium.

In certain cases, e.g., when ostia are closed or difficult to access,implant placement into one or more sinuses may be completed through thesinus wall using a sharp-tipped conduit, e.g., a needle, trocar, orangiocatheter, with or without visualization using computer image-guidedtechnology or endoscopy. Once the appropriate access point for the sinushas been determined, force is applied to the sharp-tipped conduit sothat it punctures the sinus wall. Advancement of a pusher through theconduit lumen then deposits an implant into the sinus.

FIGS. 1A-1B show examples of single implant delivery devices. Thedevices include an implant 10, a conduit 12 having a side wall 14, alumen 16, a distal portion 18, an opening 20 in the distal portion 18, atip 22, and a pusher 24. In FIG. 1A, the conduit 12 includes a ramp 26and an opening 20 positioned in the side wall 14. If delivering a solidimplant, the opening will usually be approximately twice the diameter ofthe implant. The pusher 24 is advanced distally within the lumen 16 toslidably engage the implant 10 and move it up the ramp 26 through theside wall 14 into the sinus. In FIG. 1B, the opening 20 is positioned atthe tip 22 of the conduit 12, and pusher 24 is advanced distally withinthe lumen 16 to slidably engage the implant 10 and move it through thetip 22. Although the conduit tips are shown to be blunt in the Figures,they may also be sharp and/or beveled, usually depending on the implantdelivery method.

FIG. 2A shows a device that delivers multiple implants. The device issimilar to the single implant delivery device having a conduit 28 with aside wall 30, a lumen 32, a distal portion 34, an opening 36 in thedistal portion 34, a tip 38, a pusher 40, and a ramp 42. Pusher 40 isdistally advanced a preset distance to slidably engage the most proximalimplant 44 within lumen 32. The pusher 40 is then further distallyadvanced a preset distance, e.g., a distance approximately equal to thelength of one implant, to move the most distal implant 46 throughopening 36 into the sinus.

A handle 48, as shown in FIG. 2B, may be coupled to conduit 28 such thatthe handle lumen forms a continuous lumen with the lumen 32 of theconduit 28. The pusher 40 can then slide through this continuous lumen.The handle 48 further includes an injector 42, adjacent to andlongitudinally aligned with the pusher 40, and a stepped slot 44 withvarious positions “O”, “A”, “B”, and “C”. Initially, when the injector42 is pressed, the pusher 40 is distally advanced, and a key 46 coupledto the injector 42 moves the pusher 40 between positions “O” and “A”.The distance between positions “O” and “A” is approximately equal to thelength of the dispensed implant. Pusher 40 may then be rotated to movethe key 46 from position “A” to position “B” in the stepped slot 44.Pressing the injector 42 again then moves the key along step “B” toposition “C”, and the pusher 40 a corresponding length to dispenseanother implant. Multiple implants may be delivered in this fashion,with the number of implants delivered depending on the number of stepsin the stepped slot.

Although the various implant delivery devices described above deploysolid implants, this invention also contemplates the use of the devicesto deliver various semi-solid implants and gels into the sinus. A forceapplied to a predetermined amount of a semi-solid implant or gelcomposition in the conduit, e.g., by contact with a pusher orpressurized gas, could be used to deliver the implant or gel into thesinus.

Applications

The implants may be used to treat sinusitis affecting one or more of themaxillary sinus, the frontal sinus, the ethmoidal sinus, and thesphenoidal sinus.

Furthermore, the biodegradable implants may be used to treat acute orchronic sinusitis arising from predisposing anatomical conditions,chronic allergic processes, or conditions related to infection byvarious pathogens (e.g., bacteria, fungi, and viruses).

Examples of bacteria that may cause sinusitis include Alpha-hemolyticstreptococci, Beta-hemolytic streptococci, Branhamella catarrhalis,Diptheroids, Haemophilis influenzae, Moraxella species, Pseudomonasaeroginosa, Pseudomonas maltophilia, Serratia marcescens, Staphylococcusaureus, and Streptococcus pneumoniae.

Examples of fungi that may cause sinusitis include Aspergillosis,Candida, Cryptococcus, Coccidioides, Histoplasma, and Mucor species.

The biodegradable implants may also be used to reduce inflammationresulting from a sinus procedure, typically, a sinus drainage procedure.Examples of sinus drainage procedures include, but are not limited to,widening/enlargement of a narrowed ostium, antral puncture and washout,and intranasal antrostomy. The implants may be delivered into a sinususing one of the methods previously described, usually after theprocedure is completed, but they can also be delivered into a sinusbefore the procedure or during the procedure.

If enlarging an ostium, the affected sinus will generally be accessedthrough that enlarged ostium. The biodegradable implant(s) may then bedeployed into the sinus via the enlarged ostium. With respect to antralpuncture and drainage or intranasal antrostomy, the affected sinususually will be accessed at the antral puncture site or through theantrostomy. The biodegradable implant(s) will also usually be deployedinto the sinus through the antral puncture site or antrostomy. However,if desired, the biodegradable implant(s) may be delivered through anatural ostium despite antral puncture or antrostomy being perfomed.

Method of Making the Implants

The method of preparing the implants of this invention will generallydepend on the particular therapeutic agent or matrix polymer used, formof the implant, and the release kinetics desired, but may be made by anyone of the numerous methods known in the art. For example, the implantsmay be made by such processes as compression, extrusion, molding,solvent evaporation, or solvent extraction.

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual publication, patent, or patentapplication were specifically and individually indicated to be soincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit and scope of the appended claims.

1. A biodegradable implant for treating sinusitis comprising a sustainedrelease therapeutic agent dispersed within a biodegradable matrix,wherein the biodegradable implant is sized and configured to be at leastpartially placed within a conduit and is sized and configured to bedelivered from the conduit to a paranasal sinus cavity, and has a firstsolid form prior to delivery to a paranasal sinus cavity and a secondsolid form after delivery of the biodegradable implant to a paranasalsinus cavity from the conduit, and wherein the second form has at leastone characteristic that substantially prevents clearance of the implantfrom a paranasal sinus cavity during a treatment period.
 2. Thebiodegradable implant of claim 1 wherein the at least one characteristicis size of the implant.
 3. The biodegradable implant of claim 1 whereinthe at least one characteristic is shape of the implant.
 4. Thebiodegradable implant of claim 1 wherein the at least one characteristicis density of the implant.
 5. The biodegradable implant of claim 1wherein the at least one characteristic is viscosity of the implant. 6.The biodegradable implant of claim 1 wherein the at least onecharacteristic is mucoadhesiveness of the implant.
 7. The biodegradableimplant of claim 1 wherein the sustained release therapeutic agent isselected from the group consisting of anti-infective agents,anti-inflammatory agents, and combinations thereof.
 8. The biodegradableimplant of claim 1 wherein the sustained released therapeutic agentcomprises an anti-infective agent.
 9. The biodegradable implant of claim8 wherein the anti-infective agent is selected from the group consistingof antibacterial agents, antifungal agents, antiviral agents, andantiseptics.
 10. The biodegradable implant of claim 8 wherein theanti-infective agent comprises an antibacterial agent.
 11. Thebiodegradable implant of claim 10 wherein the antibacterial agent isselected from the group consisting of aminoglycosides, amphenicols,ansamycins, β-lactams, lincosamides, macrolides, nitrofurans,quinolones, sulfonamides, sulfones, tetracyclines, and any of theirderivatives.
 12. The biodegradable implant of claim 10 wherein theantibacterial agent comprises a β-lactam.
 13. The biodegradable implantof claim 12 wherein the β-lactam comprises a penicillin.
 14. Thebiodegradable implant of claim 13 wherein the penicillin comprisesamoxicillin.
 15. The biodegradable implant of claim 1 wherein thesustained release therapeutic agent is an anti-inflammatory agent. 16.The biodegradable implant of claim 1 wherein the sustained releasetherapeutic agent comprises a steroidal anti-inflammatory agent.
 17. Thebiodegradable implant of claim 16 wherein the steroidalanti-inflammatory agent is selected from the group consisting of21-acetoxypregnenolone, alclometasone, algestone, amcinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumethasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, and any of their derivatives.
 18. The biodegradableimplant of claim 17 wherein the steroidal anti-inflammatory agentcomprises budesonide.
 19. The biodegradable implant of claim 17 whereinthe steroidal anti-inflammatory agent comprises mometasone furoate. 20.The biodegradable implant of claim 17 wherein the steroidalanti-inflammatory agent comprises beclomethasone.
 21. The biodegradableimplant of claim 1 wherein the biodegradable matrix is a biodegradablepolymer matrix.
 22. The biodegradable implant of claim 1 wherein thebiodegradable matrix comprises a mucoadhesive polymer.
 23. Thebiodegradable implant of claim 1 wherein the biodegradable matrixcomprises poly(lactic-co-glycolic)acid (PLGA) copolymer.
 24. Thebiodegradable implant of claim 23 wherein the sustained releasetherapeutic agent comprises budesonide.
 25. The biodegradable implant ofclaim 23 wherein the sustained release therapeutic agent comprisesmometasone furoate.